Alarming increase of NASH as cause of liver cancer
Authors: Ana Craciun, Helena Cortez-Pinto
Journal: Cell Reports Medicine (2022)

A very interesting recent article by Huang and colleagues evaluated the global epidemiology of liver cancer from 2010 to 2019 and showed that non-alcoholic steatohepatitis (NASH) is the fastest growing cause of hepatocellular carcinoma (HCC).1Huang D.Q. Singal A.G. Kono Y. Tan D.J. El-Serag H.B. Loomba R. Changing global epidemiology of liver cancer from 2010 to 2019: NASH is the fastest growing cause of liver cancer.Cell Metabol. 2022; 34 (Published online 2022): 969-977.e2https://doi.org/10.1016/j.cmet.2022.05.003Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar A very interesting recent article by Huang and colleagues evaluated the global epidemiology of liver cancer from 2010 to 2019 and showed that non-alcoholic steatohepatitis (NASH) is the fastest growing cause of hepatocellular carcinoma (HCC).1Huang D.Q. Singal A.G. Kono Y. Tan D.J. El-Serag H.B. Loomba R. Changing global epidemiology of liver cancer from 2010 to 2019: NASH is the fastest growing cause of liver cancer.Cell Metabol. 2022; 34 (Published online 2022): 969-977.e2https://doi.org/10.1016/j.cmet.2022.05.003Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar Non-alcoholic fatty liver disease (NAFLD) is already the most prevalent liver disease worldwide, affecting at least a quarter of the global population.2Karlsen T.H. Sheron N. Zelber-Sagi S. Carrieri P. Dusheiko G. Bugianesi E. Pryke R. Hutchinson S.J. Sangro B. Martin N.K. et al.The EASL–Lancet Liver Commission: protecting the next generation of Europeans against liver disease complications and premature mortality.Lancet. 2022; 399: 61-116https://doi.org/10.1016/S0140-6736(21)01701-3Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar All the spectrum prevalence, including advanced liver disease, will continue to increase significantly for at least another decade.3Anstee Q.M. Reeves H.L. Kotsiliti E. Govaere O. Heikenwalder M. From NASH to HCC: current concepts and future challenges.Nat. Rev. Gastroenterol. Hepatol. 2019; 16: 411-428https://doi.org/10.1038/s41575-019-0145-7Crossref PubMed Scopus (711) Google Scholar Besides that, the burden of advanced liver disease because of NAFLD will more than double during next 10 years2Karlsen T.H. Sheron N. Zelber-Sagi S. Carrieri P. Dusheiko G. Bugianesi E. Pryke R. Hutchinson S.J. Sangro B. Martin N.K. et al.The EASL–Lancet Liver Commission: protecting the next generation of Europeans against liver disease complications and premature mortality.Lancet. 2022; 399: 61-116https://doi.org/10.1016/S0140-6736(21)01701-3Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar Additionally, our vision needs to englobe the pediatric population, as we are witnessing the beginning of this silent pandemic from a young age, becoming the most common childhood chronic liver disease in many Western countries.4Bendor C.D. Bardugo A. Pinhas-Hamiel O. Afek A. Twig G. Cardiovascular morbidity, diabetes and cancer risk among children and adolescents with severe obesity.Cardiovasc. Diabetol. 2020; 19: 79https://doi.org/10.1186/s12933-020-01052-1Crossref PubMed Scopus (101) Google Scholar The development and progression of the disease so early in life will certainly increase the risk of future liver-related complications, as illustrated by the increasing number of liver transplant young registrants (<40 years old) with youth-onset NASH. Therefore, having a holistic insight of the natural history of NAFLD, from conception to adulthood, is essential to a better prevention and management.5Castillo-Leon E. Cioffi C.E. Vos M.B. Perspectives on youth-onset nonalcoholic fatty liver disease.Endocrinology, Diabetes and Metabolism. 2020; 3: e00184https://doi.org/10.1002/edm2.184Crossref PubMed Scopus (23) Google Scholar Another concern is the increasing incidence of liver cancer deaths worldwide, demonstrated in this article.1Huang D.Q. Singal A.G. Kono Y. Tan D.J. El-Serag H.B. Loomba R. Changing global epidemiology of liver cancer from 2010 to 2019: NASH is the fastest growing cause of liver cancer.Cell Metabol. 2022; 34 (Published online 2022): 969-977.e2https://doi.org/10.1016/j.cmet.2022.05.003Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar This may be partly explained by several obstacles encountered in the early diagnosis of NASH-related HCC. First, there is a higher incidence of cirrhosis absence (24–46%) in these patients and therefore they do not have routine indication for HCC surveillance based on current practice guidelines.3Anstee Q.M. Reeves H.L. Kotsiliti E. Govaere O. Heikenwalder M. From NASH to HCC: current concepts and future challenges.Nat. Rev. Gastroenterol. Hepatol. 2019; 16: 411-428https://doi.org/10.1038/s41575-019-0145-7Crossref PubMed Scopus (711) Google Scholar This has already been illustrated by the lower percentages of NASH-related HCC cases diagnosed during surveillance.3Anstee Q.M. Reeves H.L. Kotsiliti E. Govaere O. Heikenwalder M. From NASH to HCC: current concepts and future challenges.Nat. Rev. Gastroenterol. Hepatol. 2019; 16: 411-428https://doi.org/10.1038/s41575-019-0145-7Crossref PubMed Scopus (711) Google Scholar,6Tan D.J.H. Ng C.H. Lin S.Y. Pan X.H. Tay P. Lim W.H. Teng M. Syn N. Lim G. Yong J.N. et al.Clinical characteristics, surveillance, treatment allocation, and outcomes of non-alcoholic fatty liver disease-related hepatocellular carcinoma: a systematic review and meta-analysis.Lancet Oncol. 2022; 23: 521-530https://doi.org/10.1016/S1470-2045(22)00078-XAbstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar Second, HCC screening is affected in uninsured patients who do not have access to care. Also, the use of ultrasonography still misses one-third of patients at an early stage.7Singal A.G. Lampertico P. Nahon P. Epidemiology and surveillance for hepatocellular carcinoma: new trends.J. Hepatol. 2020; 72: 250-261https://doi.org/10.1016/j.jhep.2019.08.025Abstract Full Text Full Text PDF PubMed Scopus (498) Google Scholar Besides that, it is operator-dependent and more challenging in centrally overweight patients with heterogeneous livers. Third, and in consequence of the first two points, most NASH-related HCC cases are detected at advanced stage, precluding the option of curative treatment.3Anstee Q.M. Reeves H.L. Kotsiliti E. Govaere O. Heikenwalder M. From NASH to HCC: current concepts and future challenges.Nat. Rev. Gastroenterol. Hepatol. 2019; 16: 411-428https://doi.org/10.1038/s41575-019-0145-7Crossref PubMed Scopus (711) Google Scholar Furthermore, several studies have shown that these patients are less likely to receive liver transplantation due to their metabolic syndrome comorbidities. However, in case it does, the development of fatty liver or steatohepatitis on transplanted liver can potentially impact their post-transplant course.8Younossi Z.M. Henry L. Epidemiology of non-alcoholic fatty liver disease and hepatocellular carcinoma.JHEP Reports. 2021; 3: 100305https://doi.org/10.1016/j.jhepr.2021.100305Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar Huang and colleagues demonstrated that NASH and alcohol had the fastest growing age-standardized death rates (ASDRs) in liver cancer, particularly in America.1Huang D.Q. Singal A.G. Kono Y. Tan D.J. El-Serag H.B. Loomba R. Changing global epidemiology of liver cancer from 2010 to 2019: NASH is the fastest growing cause of liver cancer.Cell Metabol. 2022; 34 (Published online 2022): 969-977.e2https://doi.org/10.1016/j.cmet.2022.05.003Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar These two prevalent causes, in particular NASH, have the characteristic to share the metabolic syndrome features as risk factors for HCC in a synergistic interaction rather than being merely additive.2Karlsen T.H. Sheron N. Zelber-Sagi S. Carrieri P. Dusheiko G. Bugianesi E. Pryke R. Hutchinson S.J. Sangro B. Martin N.K. et al.The EASL–Lancet Liver Commission: protecting the next generation of Europeans against liver disease complications and premature mortality.Lancet. 2022; 399: 61-116https://doi.org/10.1016/S0140-6736(21)01701-3Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar Several independent risk factors are associated with HCC, namely heavy alcohol use, tobacco smoking, type 2 diabetes mellitus, severity of obesity, waist circumference, and socioeconomic status: the greater the number of metabolic components, the higher the risk of adverse long-term outcomes, including mortality.8Younossi Z.M. Henry L. Epidemiology of non-alcoholic fatty liver disease and hepatocellular carcinoma.JHEP Reports. 2021; 3: 100305https://doi.org/10.1016/j.jhepr.2021.100305Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar The impressive increase in NAFLD cases represents a pressing public health problem that needs to be seriously considered and managed in a global perspective. In fact, this significant increase in NAFLD is heavily related with the increased prevalence of obesity and type II diabetes. To overcome this huge burden of disease, there is need of policies and strategies oriented not only toward the patients, but also toward societies and governments at national and global levels. In the first situation, we need to prioritize all the stages of NASH spectrum, from its risk factors' control to appropriate HCC surveillance protocols.2Karlsen T.H. Sheron N. Zelber-Sagi S. Carrieri P. Dusheiko G. Bugianesi E. Pryke R. Hutchinson S.J. Sangro B. Martin N.K. et al.The EASL–Lancet Liver Commission: protecting the next generation of Europeans against liver disease complications and premature mortality.Lancet. 2022; 399: 61-116https://doi.org/10.1016/S0140-6736(21)01701-3Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar In addition, we need to shift our paradigm toward a non-invasive approach, by identifying markers that will stratify patients at risk for more cost-effective target surveillance.7Singal A.G. Lampertico P. Nahon P. Epidemiology and surveillance for hepatocellular carcinoma: new trends.J. Hepatol. 2020; 72: 250-261https://doi.org/10.1016/j.jhep.2019.08.025Abstract Full Text Full Text PDF PubMed Scopus (498) Google Scholar Hopefully, artificial intelligence will help us improve the HCC clinical care, through a better risk prediction, diagnosis, and prognostication.9Calderaro J. Seraphin T.P. Luedde T. Simon T.G. Artificial intelligence for the prevention and clinical management of hepatocellular carcinoma.J. Hepatol. 2022; 76: 1348-1361https://doi.org/10.1016/j.jhep.2022.01.014Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar Also, we need to acknowledge that a purely liver-oriented focus does not cover the multisystemic implications of NAFLD and therefore this approach requires the development of interdisciplinary and multiprofessional teams focusing on patient-centered training and care, supported by telemedicine and electronic systems, with primary care having a fundamental role through reinforced partnership and training programs.2Karlsen T.H. Sheron N. Zelber-Sagi S. Carrieri P. Dusheiko G. Bugianesi E. Pryke R. Hutchinson S.J. Sangro B. Martin N.K. et al.The EASL–Lancet Liver Commission: protecting the next generation of Europeans against liver disease complications and premature mortality.Lancet. 2022; 399: 61-116https://doi.org/10.1016/S0140-6736(21)01701-3Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar,7Singal A.G. Lampertico P. Nahon P. Epidemiology and surveillance for hepatocellular carcinoma: new trends.J. Hepatol. 2020; 72: 250-261https://doi.org/10.1016/j.jhep.2019.08.025Abstract Full Text Full Text PDF PubMed Scopus (498) Google Scholar In what concerns NAFLD and its risk factors, the most prevalent non-communicable diseases, they depend less on individual choices and more on socioeconomic and environmental conditions, exacerbated by policies that prioritize profits over health.2Karlsen T.H. Sheron N. Zelber-Sagi S. Carrieri P. Dusheiko G. Bugianesi E. Pryke R. Hutchinson S.J. Sangro B. Martin N.K. et al.The EASL–Lancet Liver Commission: protecting the next generation of Europeans against liver disease complications and premature mortality.Lancet. 2022; 399: 61-116https://doi.org/10.1016/S0140-6736(21)01701-3Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar Despite its high prevalence worldwide and its impact on health, economy, and society, NAFLD has been neglected in the national health agendas.10Lazarus J.v. Mark H.E. Villota-Rivas M. Palayew A. Carrieri P. Colombo M. Ekstedt M. Esmat G. George J. Marchesini G. et al.The global NAFLD policy review and preparedness index: are countries ready to address this silent public health challenge?.J. Hepatol. 2022; 76: 771-780https://doi.org/10.1016/j.jhep.2021.10.025Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar Therefore, we need to overlap the national and global strategic approaches to fight this alarming pandemic by implementing effective policies on food reformulation and taxation on alcohol consumption, starting with the children and adolescents. Also, there is an urgent need in changing health care funding and reimbursement process, a political problem in several countries with health inequalities.2Karlsen T.H. Sheron N. Zelber-Sagi S. Carrieri P. Dusheiko G. Bugianesi E. Pryke R. Hutchinson S.J. Sangro B. Martin N.K. et al.The EASL–Lancet Liver Commission: protecting the next generation of Europeans against liver disease complications and premature mortality.Lancet. 2022; 399: 61-116https://doi.org/10.1016/S0140-6736(21)01701-3Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar Our world has faced an unprecedented global pandemic in the last two years, with more than six million deaths worldwide because of COVID-19, forcing our societies, governments, and industries to work fast but also to join efforts toward effective solutions. Therefore, we need to keep up with these principles and focus on this not-so-new, but silent and alarming, pandemic that will continue to rise in the absence of our commitment. H.C.-P. lectures and receives advisory board fees from Intercept, Orphalan, Novo Nordisk, Roche Portugal, and EISAI. Changing global epidemiology of liver cancer from 2010 to 2019: NASH is the fastest growing cause of liver cancerHuang et al.Cell MetabolismJune 3, 2022In BriefHuang et al. estimate global and regional trends in the burden of liver cancer and the contributions of various liver disease etiologies from 2010 to 2019. They determined that NASH was the fastest growing cause of age-adjusted liver cancer deaths globally, while age-adjusted deaths from hepatitis B and C declined. Full-Text PDF Open Archive